Drug development substance properties

It is assumed during the course of drug development that any concerns related to the physical properties of the substances being formulated will be adequately researched at the appropriate moment. Unfortunately, this work is often not conducted until a crisis situation develops due to some variability in the physical properties of input materials. It is perhaps a truism that most of these problems could have been avoided had the materials received more balanced characterization. The economics of drug development, however, often interferes with the desire of the formulator to fully understand his system, and performance of the proper background work can become a casualty. 

Drugs that cause induction or inhibition of enzymes may affect the metabolism of concomitantly administered drugs, as well as of hormones and other endogenous substances. For this reason, such properties are considered undesirable, and sometimes they might constitute sufficient reason to discontinue drug development. At the very least, studies will be required to assess the magnitude of effect of likely interactions. Metabolic and toxicity studies in animals will... 

Oral dmg product formulation and manufacturing process development can use a hierarchical approach to meeting three conditions based on, in order of importance, bioavailability, stability, and manufacturability. The bioavailability of a drug product is the most critical condition and must meet established criteria or the product is not viable. Dmg substance properties such as salt form, solubility, and particle size can significantly affect pharmacokinetic and pharmacodynamic performance of a product. The dosage form platform, formulation design, and manufacturing process can also affect the PK/PD profile of a product. Therefore, all selections must maintain the required pharmacokinetic/pharmacodynamic outcome and work within these confines to achieve a stable and robust product/process. 

For ionic drugs the salt form can be considered as an alternative to increase the solubility. Drug substance usually is more soluble in aqueous media in its ionic form. Low solubility of the neutral form of the drug substance suggests the necessity to formulate it in the form of salt. The reader is referred to reference 46 for more information about the properties, selection, and use of salt forms for future drug development. Examples of commonly used salt counterions are shown in Table 12-6. 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

The current bottleneck is that many of the drug substance properties important for developability are only obtained in early development, at a time where it is late to introduce chemical changes in the structure of the molecule. 

Molecular properties may be defined as those material characteristics that theoretically can be measured for a small ensemble of individual molecules. Due to the minimal sample requirements, molecular properties are often determined at the earliest stages of drug development. Most of the molecular level techniques are spectroscopic in nature, but insofar as they are influenced by the physical state of the substance, substantial information of great use to formula-tors can be obtained from appropriately designed experiments. For example, a screening of stressed materials can be carried out on the microgram level using infrared microscopy, and the results of such work aid the preformulation characterization of a new chemical entity. 

The product development process in the pharmaceutical industry is not unlike that of other industries, in which exploratory materials are researched and developed into products, and where problems arise the analytical laboratory is called upon to provide solutions. The characterization of the physical properties of pharmaceutical solids is one of the disciplines utilized early in the drug development process. The characterization of these properties is vital to determining whether the compound under investigation is a candidate for continued development as a drug product. To facilitate the characterization of pharmaceutical solids in laboratories, a conceptual approach for this characterization has been developed (66) that uses decision trees to guide the analyst in the characterization of drug substances. 

Solid form selection involves the preparation and property evaluation of many derivatives of an active molecule. Drug substance properties of importance in the drug development process may be categorized as shown in Table 1. These properties depend on the nature of the drug substance and the final formulation. Many bioactive organic molecules contain ionizable groups such as carboxylic... 

Thus, evaluation of photoreactivity should be included in the preformulation phase during drug development, in order to optimize photochemical stability of the drug. In principle, all excipients in a parenteral formulation can influence the photochemical stability of the drug substance. Therefore, the pharmacist can possibly affect photoreactivity by changing the formulation properties (see Table 14.2). 

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